Chief Executive Officer (CEO)
45 Poplar Road
Parkville, Victoria 3052
Dear Mr. McNamee:
The Food and Drug Administration (FDA) conducted an inspection of CSL Biotherapies, located at 45 Poplar Road, Parkville, Victoria 3052, Australia, between April 19 and April 28, 2010. During the inspection, FDA investigators documented deviations from current good manufacturing practice (CGMP) requirements in the manufacture of licensed biological vaccine products and monovalent influenza bulks. These products include Afluria and Influenza A (H1N1) Monovalent Vaccine. Deviations from CGMP include the applicable requirements of Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (FD&C Act), Section 351(a) of the Public Health Service Act (PHS Act), and Title 21, Code of Federal Regulations (21 CFR) Parts 210, 211, and 600-680.
At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations that described a number of significant objectionable conditions relating to your facility’s compliance with CGMP. Significant deviations observed during the inspection include, but were not limited to, the following:
1) You failed to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications, and failed to extend the investigation to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy [21 CFR 211.192]. Specifically, your investigation dated April 16, 2010 (initiated January 5, 2010) into the formation of dark particles in Afluria Multi Dose Vials (MDV’s) is inadequate. For example:
- The investigation was conducted under procedure -(b)(4)--4161 entitled “Corrective and Preventative Actions.” This procedure was not followed in that the investigation did not “document such that there is traceability of the corrective and preventative actions from the identification of problems to implementation of solutions and the follow up to evaluate effectiveness.”
- During the investigation, a Mercury/-(b)(4)- interaction between product and vial and/or stopper was identified as a potential root cause of the particle formation. This interaction has not been evaluated so as to rule it out as a potential root cause, even though notification was received of this potential interaction on December 17, 2009 by the stopper supplier.
- Retention samples from all commercial lots have not been evaluated for the presence of black particles. Stability samples were examined for one commercial lot (Afluria lot ----(b)(4)---) and retention samples were evaluated for three commercial lots (non-USA Panvax H1N1 lots ----------------------(b)(4)--------------------) but the investigation does not document the rationale for limiting the investigation to these lots only.
2) You failed to assure that drug product containers or closures are not reactive and additive so as to alter the safety, identity strength, quality and purity of the drug beyond the official or established requirements [21 CFR 211.94(a)]. For example:
- Your firm was notified by its stopper supplier on December 17, 2009, that ----(b)(4)--- rubber --(b)(4)-- stoppers may react with thimerosal and therefore are not recommended for use with thimerosal containing products. To date your firm still utilizes these stoppers for MDV’s of vaccine containing thimerosal.
- Extractable/leachable studies representative of product and use conditions have not been conducted for the --(b)(4)-- rubber --(b)(4)-- stoppers and 5mL tubular glass -(b)(4)- vials used for thimerosal containing Afluria and H1N1 MDV products. These stopper/vial components were used to manufacture 23 lots of Afluria vaccine and 6 lots of H1N1 vaccine which were distributed to the United States.
- Extractable/leachable studies have also not been conducted for the -------(b)(4)-------- ------------------------ stoppers and ----------------(b)(4)----------- glass syringes that are used for Afluria and H1N1 single dose vaccine products. These stopper/vial components were used to manufacture 79 lots of Afluria vaccine and 46 lots of H1N1 vaccine which were distributed to the United States.
3) You failed to assure that reserve samples from representative sample lots or batches are examined at least once a year for evidence of deterioration [21 CFR 211.170(b)]. Specifically, procedure -(b)(4)--3735, entitled “Identity Testing and Visual Examination,” is inadequate in that it does not require a periodic examination of samples representative of all presentation types. Influenza MDV’s containing thimerosal have been manufactured since 2007, however, retention sample inspections for influenza vaccine conducted for 2008 through 2010 only evaluated thimerosal-free syringe presentations. Retention samples for MDV’s containing thimerosal have not been evaluated under the periodic review of retention samples.
Additionally, significant deviations in the manufacture of your monovalent influenza bulks were observed during the inspection. These deviations violate Section 501(a)(2)(B) of the FD&C Act and Section 351(a) of the PHS Act. Specific areas of concern include, but are not limited to:
Control of Components
1. You failed to establish testing procedures designed to assure components conform to appropriate standards of identity strength, quality, and purity. For example:
- There are no data to support the expiration date for thimerosal solution, stored at -(b)(4)- for -(b)(4)- months, used in the manufacture of Afluria and HlNl vaccines.
- There are no data to support the -(b)(4)- expiation date of thimerosal raw material under your actual use and storage conditions. The raw material is stored in the -----(b)(4)----- container at ------(b)(4)-------- and is opened and closed multiple times for dispensing in a Class -(b)(4)- area.
We acknowledge receipt of your written response dated May 14, 2010, which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection. We also acknowledge your commitments made in your response to address the items listed on the Form FDA 483.
We have reviewed your responses and have the following specific comments. The items are numbered to correspond to the observations listed on the Form FDA 483.
Please provide a summary of your action plan to address the medium risk assigned to the -(b)(4)------- fittings by your firm for review. Include within this summary a copy of the extractables study conducted under worst case conditions and your decision/justification in the determination of the requirement for a leachable study based on the results of the extractable study as described in your response.
Neither the above deviations, nor the observations listed on the Form FDA 483 presented to your firm at the conclusion of the inspection, are intended to be an all-inclusive list of deviations at your establishment. It is your responsibility to ensure compliance with all requirements of the laws and regulations administered by FDA.
We would like to meet with you and other senior management at CSL Biotherapies to further discuss the issues cited in this letter and how you will address them going forward.. Given the potential contributions of safe, pure, and potent vaccines to the public health, we encourage frequent interactions between your technical staff and FDA in an effort to help CSL Biotherapies move forward with corrective actions as rapidly as possible.
Your reply should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20852-1448. To schedule a meeting at your earliest convenience, please contact Robert McElwain, Consumer Safety Officer, in the Division of Case management at (301) 827-6196.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research